AGM STUDIES: A crucial element in understanding the pathogenesis of lentiviral infections is to compare and contrast parameters between progressive and non-progressive infections. Indeed, elucidating the mechanisms underlying AIDS resistance of SIV-infected natural hosts may provide critical information to better understand AIDS pathogenesis. To date, >40 primate lentiviruses have been found to naturally infect African nonhuman primate hosts at high prevalence levels. In general, SIVs infecting African species evolved through host-dependent evolution, meaning that they have infected different NHP species for thousands, or hundreds of thousands, of years, possibly since primate speciation. During this long history, SIVs and their natural hosts evolved to coexistence, with the African NHPs infected with their species-specific viruses generally not showing signs of SIV-induced disease or simian AIDS. During this report period we have shown that homeostatic cytokines can be safely delivered to NHPs many times and that these maintain effectiveness in vivo. When administered to African green monkeys these cytokines stimulate proliferation of CD4 T cells which causes their downregulation of CD4 expression. Moreover we were able to show that SIVagm viruses can utilize noncanonical co-receptors (which are not used by other SIV viruses or HIV) and we were able to sequence the genome of African green monkeys. MICROBIAL TRANSLOCATION STUDIES Progressive lentiviral infection of primates is associated with a multifaceted activation of the immune system. This chronic immune activation has been shown to be tightly associated with HIV and SIV disease progression. We recently showed that one of the major causes of this chronic immune activation was microbial translocation. During the acute phase of infection the structural and immunological barrier of the gastrointestinal tract are damaged and microbial products consequently translocate from the lumen into peripheral circulation. In circulation these microbial products can stimulate the adaptive and innate arms of the immune system. Indeed, we found significant correlations between microbial translocation and measures of immune activation in chronically HIV/SIV-infected individuals. During this report period we have shown that T cells which recognize metabolites produced by particular types of bacteria are decreased in frequencies and are dysfunctional in peripheral blood and tissues of progressively SIV-infected Asian macaques and we have shown that microbial translocation is decreased with concomitant improved immunological reconstitution if ARVs are supplemented with IL-21 and live, beneficial, probiotic organisms. We believe these data will lead to novel therapeutic interventions which improve the prognosis of HIV-infected individuals.